A 1β-methylcarbapenem compound is one of the antibacterial agents attracting the most attention because it shows an excellent antibacterial effect on a wide variety of pathogenic organisms and is excellent in stability in vivo. Accordingly, various research and development have been made energetically in recent years attempting to produce the drugs for oral administration. Processes for producing a 1β-methylcarbapenem compound for oral administration, which are generally used at present, include the following processes.
For example, there is described a process in Japanese Unexamined Patent Application Publication No. 8-53453 and J. Antibiot., p. 429-439, 1997, which comprises the steps of reacting a compound represented by formula (6):
with each of various thiol compounds (R—SH) to synthesize a compound represented by formula (7):
wherein R denotes a thiol residue; eliminating a p-nitrobenzyl group, a protective group, from the compound represented by formula (7), for example, by hydrogenolysis or reduction by a zinc powder to convert it to a compound represented by formula (8):
wherein R denotes a thiol residue; and subjecting the carboxylic moiety of the resulting compound (8) to pivaloyloxymethylation to produce a compound represented by formula (9):
wherein R denotes a thiol residue, and But denotes a tert-butyl group.
As the compounds represented by formula (9), for example, in Japanese Unexamined Patent Application Publication Nos. 8-53453 and 10-195076 is described a compound represented by formula (10):
; in J. Antibiot., P. 429-439, 1997 and Japanese Unexamined Patent Application Publication No. 10-130270 is described a compound represented by formula (11):
; and in Japanese Unexamined Patent Application Publication No. 10-152491 is described a compound represented by formula (12):
All of these compounds are synthesized by the above-described process.
However, when 1β-methylcarbapenem compound for oral administration is produced by these production processes, it is necessary to exchange the protecting group of carboxylic acid through multistep reactions, which is ineffective; and relatively expensive thiol compounds, each of which is related to a thiol residue in a final product, are used in the initial stage of synthesis, which is disadvantageous in terms of production cost. These have been regarded as problems in the above production processes.
Furthermore, in Japanese Unexamined Patent Application Publication Nos. 8-59663 and 2000-344774 is described a process for producing a compound represented by formula (15):
wherein R5 denotes a hydroxy-protecting group; R6 denotes a thiol residue contained in a 1β-methylcarbapenem compound, a product; and R7 denotes an organic group,
by the steps of synthesizing a compound represented by formula (14):
wherein R5, R6 and R7 each denote the same as described above; and R8, R9 and R0 each denote a lower alkoxy group having 1 to 4 carbon atoms, or any one of R8, Rg and R0 denotes an alkyl group having 1 to 4 carbon atoms and remaining two each denote a lower alkoxy group having 1 to 4 carbon atoms,
from a compound represented by formula (13):
wherein R5, R6 and R7 each denote the same as described above, and
cyclizing the compound represented by formula (14).
However, in this production process also, relatively expensive thiol compounds, each of which is related to a thiol residue in a final product, are used in the initial stage of synthesis in the same manner as described above. Therefore, the process is also disadvantageous in terms of production cost, which has been regarded as a problem.
Furthermore, in J. Org. Chem., vol. 61, P. 7889-7894, 1996 and Japanese Unexamined Patent Application Publication No. 5-279367 is described a compound represented by formula (16):
wherein Me denotes a methyl group; and But denotes the same as described above. It may be considered that the compound is converted to a 1β-methylcarbapenem compound by allowing it to react with any of various thiol compounds and by deprotection of a hydroxy group. However, since a tert-butyldimethylsilyl group is used as the hydroxy-protecting group in the above compound (16), it is necessary to use a reagent that influences other functional groups in order to perform deprotection at the hydroxylic moiety, as illustrated in Protective Groups in Organic Synthesis (J Wiley & Sons, New York), P. 44-46, 1981. This is a problem in terms of yields or the like. The present inventors have made various studies on the method of deprotection, and have found that it is difficult to perform deprotection easily and efficiently.
Under the circumstances as described above, the development of a efficient process for producing a 1β-methylcarbapenem compound for oral administration, wherein the process is advantageous in terms of production cost, has been desired.